Resistance breakers: a novel approach to tackle biofilm associated infections and antimicrobial resistance.

Antimicrobial resistance (AMR) has emerged as one of the greatest global health concerns and its threat to effective treatment of infectious diseases is accelerating. Biofilms remain a major contributor to antimicrobial resistance and persistence of infections. Bacterial biofilms are sessile communities of bacteria surrounded by a self-produced extracellular polymeric substance (EPS). Bacterial cells in biofilms are less susceptible to conventional antibiotics and to host immune effector mechanisms as the cells are protected by the EPS, exhibit altered gene expression as well as heterogeneity in metabolic and physiological states compared to planktonic cells. This poses a challenge for antimicrobial treatments and the development of innovative antibiofilm strategies to combat biofilm associated infections and resistance. This review explores resistance in bacterial biofilms and the recent advancements in resistance breakers: compounds that can inhibit or disrupt mechanisms of resistance to restore clinical efficacy of antibiotics. Different categories of resistance breakers are discussed including matrix disruptors, efflux pump inhibitors, enzyme inhibitors, membrane permeabilizers, quorum sensing inhibitors, and metabolic modulators. Finally, we discuss perspectives on existing translational and clinical challenges.